Aims: Identifying preoperative risk factors in older patients becomes more important to reduce adverse functional outcome. This study investigated the association between preoperative medication... Show moreAims: Identifying preoperative risk factors in older patients becomes more important to reduce adverse functional outcome. This study investigated the association between preoperative medication use and functional decline in elderly cardiac surgery patients and compared polypharmacy as a preoperative screening tool to a clinical frailty assessment.Methods: This sub-study of the Anaesthesia Geriatric Evaluation study included 518 patients aged ≥70 years undergoing elective cardiac surgery. The primary outcome was functional decline, defined as a worse health-related quality of life or disability 1 year after surgery. The association between polypharmacy (i.e. ≥5 prescriptions and <10 prescriptions) or excessive polypharmacy (i.e. ≥10 prescriptions) and functional decline was investigated using multivariable Poisson regression. Discrimination, calibration and reclassification indices were used to compare preoperative screening tools for patient selection.Results: Functional decline was reported in 284 patients (55%) and preoperative polypharmacy and excessive polypharmacy showed higher risks (adjusted relative risk 1.57, 95% confidence interval [CI] 1.23-1.98 and 1.93, 95% CI 1.48-2.50, respectively). Besides cardiovascular medication, proton-pump inhibitors and central nervous system medication were significantly associated with functional decline. Discrimination between models with polypharmacy or frailty was similar (area under the curve 0.67, 95% CI 0.61-0.72). The net reclassification index improved when including polypharmacy to the basic model (17%, 95% CI 0.06-0.27).Conclusion: Polypharmacy is associated with functional decline in elderly cardiac surgery patients. A preoperative medication review is easily performed and could be used as screening tool to identify patients at risk for adverse outcome after cardiac surgery. Show less
Vlies, E. van der; Smits, A.B.; M. los; Hengel, M. van; Bos, W.J.W.; Dijksman, L.M.; ... ; Noordzij, P.G. 2020
Objective: To determine the influence of a preoperative multidisciplinary evaluation for frail older patients with colorectal cancer (CRC) on preoperative decision making and postoperative outcomes... Show moreObjective: To determine the influence of a preoperative multidisciplinary evaluation for frail older patients with colorectal cancer (CRC) on preoperative decision making and postoperative outcomes.Background: Surgery is the main treatment for CRC. Older patients are at increased risk for adverse outcomes. For complex surgical cases, a multidisciplinary team (MDT) approach has been suggested to improve postoperative outcome. Evidence is lacking.Methods: Historical cohort study from 2015 to 2018 in surgical patients >= 70 years with CRC. Frailty screening was used to appraise the somatic, functional and psychosocial health status. An MDT weighed the risk of surgery versus the expected gain in survival to guide preoperative decision making and initiate a prehabilitation program. Primary endpoint was the occurrence of a Clavien-Dindo (CD) Grade III-V complication. Secondary endpoints included the occurrence of any complication (CD II-V), length of hospital stay, discharge destination, readmission rate and overall survival.Results: 466 patients were included and 146 (31.3%) patients were referred for MDT evaluation. MDT patients were more often too frail for surgery compared to non-MDT patients (10.3% vs 2.2%, P = .01). Frailty was associated with overall mortality (aOR 2.6 95% CI 1.1-6.1). Prehabilitation was more often performed in MDT patients (74.8% vs 23.4% in non-MDT patients). Despite an increased risk, MDT patients did not suffer more postoperative complications (CD III-V) than non-MDT patients (14.9% vs 12.4%; P = .48). Overall survival was worse in MDT patients (35 (32-37) vs 48 (47-50) months in non-MDT patients; P < .01).Conclusions: Implementation of preoperative MDT evaluation for frail patients with CRC improves risk stratification and prehabilitation, resulting in comparable postoperative outcomes compared to non-frail patients. However, frail patients are at increased risk for worse overall survival. (C) 2020 Published by Elsevier Ltd. Show less
Background: The impact of weight on pharmacokinetics of gentamicin was recently elucidated for (morbidly) obese individuals with normal renal function.Objectives: To characterize the... Show moreBackground: The impact of weight on pharmacokinetics of gentamicin was recently elucidated for (morbidly) obese individuals with normal renal function.Objectives: To characterize the pharmacokinetics of gentamicin in real-world obese patients, ultimately to develop dose recommendations applicable across the entire obese population.Methods: In two Large Dutch hospitals, all admitted patients with BMI >= 25 kg/m(2) with at Least one gentamicin administration, at Least one gentamicin and at Least one creatinine serum concentration measurement were included. Data from one hospital, obtained from electronic health records, combined with prospective data of non-obese and morbidly obese people with normal renal function, served as the training dataset, and data from the second hospital served as the external validation dataset.Results: In the training dataset [1187 observations from 542 individuals, total body weight (TBW) 52-221 kg and renal function (CKD-EPI) 5.1-141.7 mL/min/1.73 m(2)], TBW was identified as a covariate on distribution volume, and de-indexed CKD-EPI and ICU stay on clearance (all P< 0.001). Clearance was 3.53 L/h and decreased by 0.48 L/h with each 10 mL/min reduction in de-indexed CKD-EPI. The results were confirmed in the external validation (321 observations from 208 individuals, TBW 69-180 kg, CKD-EPI 5.3-130.0 mL/min/1.73 m(2)).Conclusions: Based on the study, we propose specific mg/kg dose reductions with decreasing CKD-EPI values for the obese population, and extension of the dosing interval beyond 24 h when CKD-EPI drops below 50 mL/min/1.73 m(2). In ICU patients, a 25% dose reduction could be considered. These guidelines can be used to guide safe and effective dosing of gentamicin across the real-world obese population. Show less
Vlies, E. van der; M. los; Stijns, P.E.F.; Hengel, M. van; Blaauw, N.M.S.; Bos, W.J.W.; ... ; Noordzij, P.G. 2020
Objective To determine the value of preoperative frailty screening in predicting postoperative severe complications and 1-year mortality in patients undergoing radical cystectomy (RC). Patients and... Show moreObjective To determine the value of preoperative frailty screening in predicting postoperative severe complications and 1-year mortality in patients undergoing radical cystectomy (RC). Patients and Methods Prospective cohort single-centre study in patients undergoing RC from September 2016 to December 2017. Preoperative frailty screening was implemented as standard care and was used to guide shared decision-making during multidisciplinary team meetings. Frailty screening consisted of validated tools to assess physical, mental and social frailty. Patients were considered frail when having two or more frailty characteristics. The primary endpoint was the composite of a severe complication (Clavien-Dindo Grade III-V) within 30 days and 1-year all-cause mortality. The secondary endpoints included any complication (Clavien-Dindo II-V), length of stay, readmission within 30 days, and all-cause mortality. Logistic regression analysis and the concordance statistic (c-statistic) were used to describe the association and predictive value of preoperative frailty screening. Results A total of 63 patients were included; 39 (61.9%) were considered frail. Preoperative frailty was associated with a seven-fold increased risk of a severe complication or death 1 year after RC [adjusted odds ratio (OR) 7.36, 95% confidence interval (CI) 1.7-31.8; 22 patients]. Compared to the American Society of Anesthesiologists (ASA) score and Charlson Comorbidity Index, frailty showed the best model performance (NagelkerkeR(2)0.20) and discriminative ability(c-statistic 0.72,P < 0.01) for the primary endpoint. After adding frailty to the conventional ASA risk score, the c-statistic improved by 11% (P < 0.01). Overall survival was significantly worse in frail patients (23.2 months, 95% CI 18.7-30.1) vs non-frail patients (32.9 months, 95% CI 30.0-35.9;P = 0.01). Conclusions Frail patients undergoing RC are at high risk of postoperative adverse outcomes including death. Preoperative frailty screening improves preoperative risk stratification and may be used to guide patient selection for RC. Show less
Background: The prevalence of obesity has shown a dramatic increase over recent decades. Obesity is associated with underdosing of antimicrobial drugs for prophylaxis and treatment. Posaconazole is... Show moreBackground: The prevalence of obesity has shown a dramatic increase over recent decades. Obesity is associated with underdosing of antimicrobial drugs for prophylaxis and treatment. Posaconazole is a broad-spectrum triazole antifungal drug Licensed for prophylaxis and treatment of invasive fungal infections. It is unclear how posaconazole should be dosed in obese patients.Methods: We performed a prospective study investigating the pharmacokinetics of posaconazole in morbidly obese (n = 16) and normal-weight (n = 8) subjects, with a weight ranging between 61.4 and 190 kg, after a 300 or 400 mg IV dose. Population pharmacokinetic modelling was used to assess the effect of body size on posaconazole pharmacokinetics. ClinicalTrials.gov Identifier: NCT03246386.Results: Total body weight best predicted changes in CL and V. Model-based simulations demonstrated that, for treatment of fungal infections, a daily IV dose of 300 mg will result in a PTA of >= 90% in individuals up to 140 kg, after which both twice daily Loading and the daily maintenance dose should be increased to 400 mg. For prophylaxis, a 300 mg IV dose is adequate in patients up to 190 kg.Conclusions: Body size has a significant impact on posaconazole CL and V, resulting in a Lower exposure in obese subjects compared with normal-weight subjects. For therapeutic use of posaconazole, a dose increase is required in patients above 140 kg. For prophylaxis, a 300 mg IV dose is adequate. For oral treatment, these recommendations can act as a starting point followed by therapeutic drug monitoring. Show less
AIMS:For vancomycin treatment in obese patients, there is no consensus on the optimal dose that will lead to the pharmacodynamic target (AUC 400-700 mg*h L-1 ). This prospective study quantifies... Show moreAIMS:For vancomycin treatment in obese patients, there is no consensus on the optimal dose that will lead to the pharmacodynamic target (AUC 400-700 mg*h L-1 ). This prospective study quantifies vancomycin pharmacokinetics in morbidly obese and non-obese individuals, in order to guide vancomycin dosing in the obese.METHODS:Morbidly obese individuals (n=20) undergoing bariatric surgery and non-obese healthy volunteers (n=8) (total body weight (TBW) 60.0-234.6 kg) received a single vancomycin dose (obese: 12.5 mg kg-1 , maximum 2500 mg; non-obese: 1000 mg) with plasma concentrations measured over 48 hours (11-13 samples per individual). Modelling, internal validation, external validation using previously published data and simulations (n=9950 individuals, TBW 60-230 kg) were performed using NONMEM.RESULTS:In a three-compartment model, peripheral volume and clearance increased with TBW (both p<0.001), which was confirmed in the external validation. A dose of 35 mg kg-1 per day (maximum 5500 mg/day) resulted in a >90% target attainment (AUC>400 mg*h L-1 ) in individuals up to 200 kg, with corresponding trough concentrations of 5.7-14.6 mg L-1 (twice daily dosing). For continuous infusion, a loading dose of 1500 mg is required for steady state on day 1.CONCLUSIONS:In this prospective, rich sampling pharmacokinetic study, vancomycin clearance was well predicted using TBW. We recommend that in obese individuals without renal impairment, vancomycin should be dosed as 35 mg kg-1 per day (maximized at 5500 mg/day). When given over two daily doses, trough concentrations between 5.7-14.6 mg L-1 correspond to the target exposure in obese individuals. Show less
BACKGROUND AND OBJECTIVE:Gentamicin is an aminoglycoside antibiotic predominantly used in bloodstream infections. Although the prevalence of obesity is increasing dramatically, there is no... Show moreBACKGROUND AND OBJECTIVE:Gentamicin is an aminoglycoside antibiotic predominantly used in bloodstream infections. Although the prevalence of obesity is increasing dramatically, there is no consensus on how to adjust the dose in obese individuals. In this prospective clinical study, we study the pharmacokinetics of gentamicin in morbidly obese and non-obese individuals to develop a dosing algorithm that results in adequate drug exposure across body weights.METHODS:Morbidly obese subjects undergoing bariatric surgery and non-obese healthy volunteers received one intravenous dose of gentamicin (obese: 5 mg/kg based on lean body weight, non-obese: 5 mg/kg based on total body weight [TBW]) with subsequent 24-h sampling. All individuals had a normal renal function. Statistical analysis, modelling and Monte Carlo simulations were performed using R version 3.4.4 and NONMEM® version 7.3.RESULTS:A two-compartment model best described the data. TBW was the best predictor for both clearance [CL = 0.089 × (TBW/70)0.73] and central volume of distribution [Vc = 11.9 × (TBW/70)1.25] (both p < 0.001). Simulations showed how gentamicin exposure changes across the weight range with currently used dosing algorithms and illustrated that using a nomogram based on a 'dose weight' [70 × (TBW/70)0.73] will lead to similar exposure across the entire population.CONCLUSIONS:In this study in morbidly obese and non-obese individuals ranging from 53 to 221 kg we identified body weight as an important determinant for both gentamicin CL and Vc. Using a body weight-based dosing algorithm, optimized exposure across the entire population can be achieved, thereby potentially improving efficacy and safety of gentamicin in the obese and morbidly obese population.TRIAL REGISTRATION:Registered in the Dutch Trial Registry (NTR6058). Show less
Hoogd, S. de; Valkenburg, A.J.; Dongen, E.P.A. van; Daeter, E.J.; Rosmalen, J. van; Dahan, A.; ... ; Knibbe, C.A.J. 2019
Earlier reports of increased pain sensitivity 1 year after the use of remifentanil could not be confirmed in this randomised study using Quantitative Sensory Testing. This indicates that... Show moreEarlier reports of increased pain sensitivity 1 year after the use of remifentanil could not be confirmed in this randomised study using Quantitative Sensory Testing. This indicates that remifentanil plays a minor role in the development of chronic thoracic pain. Still, the relatively high incidence of chronic thoracic pain and its accompanying impact on quality of life remain challenging problems.\nBoth warm and cold detection, and pain thresholds, were not significantly different between the remifentanil and fentanyl groups 3 days and 12 months after surgery (P > 0.05). No significant predictors for altered pain sensitivity were identified.\nThe study was registered at EudraCT (ref: 2013-000201-23) and ClinicalTrials.gov (https://clinicaltrials.gov/ct2/show/NCT02031016).\nThe clinical relevance of the suggested hyperalgesic effects of remifentanil is still unclear, especially in the long term.\nThe current study evaluated the impact of remifentanil on thermal thresholds 3 days and 12 months after surgery, measured with Quantitative Sensory Testing.\nA single-blind, randomised controlled trial.\nA tertiary care teaching hospital in The Netherlands, from 2014 to 2016.\nA total of 126 patients aged between 18 and 85 years, undergoing cardiothoracic surgery via sternotomy (coronary artery bypass grafts and/or valve replacement) were included. Exclusion criteria were BMI above 35 kg m, history of cardiac surgery, chronic pain conditions, neurological conditions, allergy to opioids or paracetamol, language barrier and pregnancy.\nPatients were allocated randomly to receive intra-operatively either a continuous remifentanil infusion or intermittent intra-operative fentanyl as needed in addition to standardised anaesthesia with propofol and intermittent intravenous fentanyl at predetermined time points.\nWarm and cold detection and pain thresholds 3 days and 12 months after surgery. In addition the use of remifentanil, presence of postoperative chronic pain, age, opioid consumption and pre-operative quality of life were tested as a predictor for altered pain sensitivity 12 months after surgery.\nCONCLUSION\nRESULTS\nTRIAL REGISTRATION\nBACKGROUND\nOBJECTIVE\nDESIGN\nSETTING\nPATIENTS\nINTERVENTIONS\nMAIN OUTCOME MEASURES Show less
The clearance of cytochrome P450 (CYP) 3A substrates is reported to be reduced with lower age, inflammation and obesity. As it is unknown what the overall influence is of these factors in the case... Show moreThe clearance of cytochrome P450 (CYP) 3A substrates is reported to be reduced with lower age, inflammation and obesity. As it is unknown what the overall influence is of these factors in the case of obese adolescents vs. morbidly obese adults, we studied covariates influencing the clearance of the CYP3A substrate midazolam in a combined analysis of data from obese adolescents and morbidly obese adults. ) was evaluated. was proposed. is explained by increased liver blood flow. The approach characterising the influence of obesity in the paediatric population we propose here may be of value for use in future studies in obese adolescents. BACKGROUND METHODS RESULTS DISCUSSION Show less
Hoogd, S. de; Välitalo, P.A.J.; Dahan, .A.; Kralingen, S. van; Coughtrie, M.M.W.; Dongen, E.P.A. van; ... ; Knibbe, C.A.J. 2017
Obesity is associated with many pathophysiological changes that may result in altered drug metabolism. The aim of this study is to investigate the influence of obesity on the pharmacokinetics of... Show moreObesity is associated with many pathophysiological changes that may result in altered drug metabolism. The aim of this study is to investigate the influence of obesity on the pharmacokinetics of morphine, morphine-3-glucuronide (M3G), and morphine-6-glucuronide (M6G) through a combined analysis in morbidly obese patients and non-obese healthy volunteers.\n for 1 h. Population pharmacokinetic modeling was performed using NONMEM 7.2.\nIn morbidly obese patients, elimination clearance of M3G and M6G was decreased substantially compared with healthy volunteers (p < 0.001). Regarding glucuronidation, only a slight decrease in the formation of M6G and a delay in the formation of M3G was found (both p < 0.001). Obesity was also identified as a covariate for the peripheral volume of distribution of morphine (p < 0.001).\nMetabolism of morphine is not altered in morbidly obese patients. However, decreased elimination of both M3G and M6G is evident, resulting in a substantial increase in exposure to these two metabolites. A rational explanation of this finding is that it results from alterations in membrane transporter function and/or expression in the liver. ClinicalTrials.gov identifier: NCT01097148.\nINTRODUCTION\nMETHODS\nRESULTS\nCONCLUSION Show less
Previous studies reveal an elevated suicide rate for anaesthesiologists. We sought to examine anaesthesiologist suicide mortality and its underlying explanatory factors. Two studies were conducted... Show morePrevious studies reveal an elevated suicide rate for anaesthesiologists. We sought to examine anaesthesiologist suicide mortality and its underlying explanatory factors. Two studies were conducted in order to establish the suicide mortality figures among Dutch anaesthesiologists and to investigate life events, workrelated stress, psychological problems and alcohol- and drug abuse in relation to suicidal ideation. The results suggest that suicide mortality in anaesthesiologists in The Netherlands is elevated, and comparable to that in other Western countries, but small numbers prevent robust testing of this difference. Anaesthesiologists are more likely than the general population to experience sleeping problems and suicidal ideation; male anaesthesiologists are more likely to suffer from depression. The prevalence of suicide among this population may be related to a high prevalence of psychological problems, in addition to the knowledge and availability of means. Areas of suicide prevention among this group are discussed. Show less
